TDM OF DIGOXIN

1. TDM OF DIGOXIN Dr S Sirisha DEPARTMENT OF PHARMACY PRACTICE

2. INTRODUCTION • Digoxin continues to have an important role in the control of ventricular rate with atrial fibrillation, and as a positive inotropic agent in heart failure • Therapeutic drug monitoring (TDM) for digoxin was introduced more than 30 years ago, and resulted in a marked reduction in the incidence of digoxin toxicity • However, despite a long experience of TDM with this drug, the way in which TDM is performed is often inappropriate • These problems most likely relate to a lack of knowledge about the practice of digoxin TDM

3. INDICATIONS FOR THERAPEUTIC DRUG MONITORING OF DIGOXIN • Confirmation of toxicity • Assessing the effect of factors altering pharmacokinetics • Therapeutic failure • Medication compliance

4. CONFIRMATION OF TOXICITY • The need to measure digoxin concentrations for confirmation of toxicity is related to the low therapeutic index of digoxin • The recommended therapeutic range (1.0 to 2.5 nmol/l or 0.5-2.0 ng/mL) reflects the significant increase in risk of toxicity that occurs with serum concentrations over 2.6 nmol/l, and which is almost invariable once the concentration exceeds 3.8 nmol/l • Symptoms of toxicity includenausea, vomiting, diarrhoea, abdominal pain, confusion, dizziness, agitation, arrhythmias, heart block and various visual symptoms • Toxicity is generally a clinical diagnosis supported by an elevated digoxin concentration, but it is also apparent that clinical suspicion of toxicity correlates poorly with high concentrations • This is not surprising because, many of the symptoms of digoxin toxicity are non-specific and are frequently present in acutely ill patients in general

5. ASSESSING THE EFFECT OF FACTORS ALTERING PHARMACOKINETICS • A number of different factors influence the pharmacokinetics of digoxin in an individual, but renal function is by far the major contributor • Maintenance dose estimation based on calculation of the patient’s creatinine clearance, using a formula such as the Cockcroft and Gault equation, will usually result in an appropriate dose in most patients • However, renal function alone does not explain all the variance in serum digoxin concentrations • A computer programme that included renal function as a variable to predict an appropriate digoxin dose for individual patients performed only marginally better than physician attempts • Some of the unpredictable relationship between dose and serum concentration of digoxin may be explained by genetic polymorphism of the p-glycoprotein gene

6. ASSESSING THE EFFECT OF FACTORS ALTERING PHARMACOKINETICS… • P-glycoprotein is involved in the transport of digoxin into the body in the gastrointestinal tract, and out of the body in the renal tubules • Mutations within this gene have been shown to alter the bioavailability and renal clearance of digoxin • Drug interactions also affect serum concentrations of digoxin, usually through competitive inhibition of p-glycoprotein activity • Because sources of variability other than renal function are less predictable or measurable, adjusting an individual’s maintenance dose on the basis of their creatinine clearance remains the best starting point for dose individualization

7. DRUG INTERACTIONS FOR DIGOXIN Drugs that increase digoxin concentration: • Diuretics: Spironolactone, Amiloride, Triamterene • Antiarrhythmics: Quinidine, Amiodarone • Calcium Antagonists: Verapamil, Minimal Effect With Nifedipine and Diltiazem • HMG CoA Reductase Inhibitors: Atorvastatin in high dose (80 Mg Daily) • Macrolide Antibiotics: Erythromycin, Clarithromycin, Roxithromycin • Benzodiazepines: Alprazolam Drugs that decrease digoxin concentration: • Rifampicin: Induces P-glycoprotein-mediated tubular secretion • Liquid Antacids: Reduce Digoxin absorption Drugs that increase digoxin effect: • Diuretics: via hypokalaemia

8. THERAPEUTIC FAILURE • Digoxin TDM is also considered to be indicated in situations of apparent therapeutic failure, although the validity of the therapeutic range in terms of efficacy is unclear • In terms of improving rate control in chronic atrial fibrillation, a review of the literature found only a weak correlation between digoxin concentration and ventricular rate • This is not surprising as the number of other influences on the atrio-ventricular node, such as altered sympathetic drive with other comorbidities (e.g.: sepsis, hypoxia) • However, TDM for individual patients may be useful to detect patients with a low digoxin concentration and who may benefit from an increase in digoxin dose, as opposed to those with higher concentrations who are likely to develop toxicity symptoms only from an increase in dose

9. THERAPEUTIC FAILURE • In congestive cardiac failure there is increasing evidence that concentrations lower than the currently recommended limit of the therapeutic range (<1.0 nmol/l) may be as efficacious as higher concentrations • Results from the PROVED and RADIANCE trials, and their subsequent re-analysis, suggest that digoxin concentrations between 0.6 and 1.2 nmol/l may be as efficacious, and less pro-arrythmic, than higher concentrations in patients with heart failure • These trials suggest that for heart failure at least, the lower end of the therapeutic range could be lowered to 0.6 nmol/l

10. APPROPRIATE SAMPLING TIME • Digoxin concentrations should be measured at least eight hours following an oral dose of digoxin and ideally when concentrations have reached steady-state • Understanding of the reasons behind these recommendations requires an understanding of the pharmacokinetic profile of digoxin • Digoxin is well absorbed, with peak serum concentrations occurring within one hour • A large volume of distribution (4 –7 l/kg) reflects that digoxin concentrates in the tissues, with the active site being within myocardial and other cells • Redistribution from serum to tissue takes at least six to eight hours • Steady state conditions of digoxin had to have been reached (defined as 5 half-lives after digoxin was initiated or after digoxin dose adjustment; i.e. 7 days in patients with normal renal function; t½: 36 hrs; 4-6 days in RF)

11. APPROPRIATE SAMPLING TIME… Digoxin concentration profile following an oral dose • Samples taken within eight hours of a dose will falsely imply elevated serum concentrations, and inappropriate dose reduction may result • A number of dramatic cases occurred where an apparently very high digoxin concentration was an artifact of early sampling

12. DOSE ADJUSTMENT • Serum digoxin concentrations should be interpreted within the clinical context • It is generally accepted that when the concentration is above the therapeutic range, the dose should be reduced even in the absence of obvious toxicity • This is because the patient is at risk of arrhythmia and there is probably no additional efficacy associated with a high concentration • On the other hand, toxicity can occur with concentrations within the therapeutic range • This may result from several known factors that change tissue sensitivity to digoxin and alter the therapeutic index

13. DOSE ADJUSTMENT… Factors altering digoxin sensitivity and the likelihood of toxicity • The period of time that digoxin should be withheld following an episode of toxicity depends upon how high the concentration is, and the half-life of digoxin in that patient • In a patient with normal renal function (half-life approximately 30 h) and a concentration of 3.0 nmol/l, the digoxin should be withheld for 1–2 days before restarting at the appropriately altered dose, as this will allow the concentration to drop to within the therapeutic range • In renal impairment with a prolonged digoxin half-life, doses may need to be withheld for several days

14. DOSE ADJUSTMENT… • When the measured digoxin concentration is low, options include stopping treatment, increasing the dose or making no change • If the indication for therapy is rate control, and the current ventricular rate is appropriate in the presence of low digoxin concentrations, a trial without digoxin may be appropriate • If ventricular rate is not controlled, a dose increase is usually indicated • However, poor rate control may be related to other acute illness processes, and treatment of the underlying condition may be all that is required • If the concentration is above 0.6 nmol/l and the indication is heart failure that is now controlled, the dose may not need to be adjusted

15. DOSE ADJUSTMENT… • Dose adjustment for apparent therapeutic failure should ideally only be performed following a digoxin concentration measured at steady-state • A change in dose will normally result in a proportional change in digoxin concentration, e.g.: doubling the dose will double the digoxin concentration, and halving the dose will halve the concentration (assuming stable renal function and no new drug interactions) • In situations where there is changing renal function, the adjustment can be estimated by calculating the change in creatinine clearance using the Cockcroft and Gault formula • For example, a halving of the patient’s renal function from baseline means that only half of the initial maintenance dose will be required to maintain the same steady-state concentration

16. CONCLUSION • Digoxin remains a classical drug for which therapeutic drug monitoring may be useful • It has a narrow therapeutic index, complex pharmacokinetics, and a dose-response relationship, at least for toxicity • However, therapeutic drug monitoring is only useful if performed correctly • Particular attention needs to be paid to the timing of sampling with respect to dosing, the presence or otherwise of steady-state conditions, and the half-life and its consequences for dosing in the individual patient